Aminoalkanol esters and their pharmaceutically acceptable acid-addition salts

ABSTRACT

Aminoalkanol esters of the formula: WHEREIN R is hydrogen or phenyl, R&#39;&#39; is hydrogen or alkyl having one to four carbon atoms, R&#39;&#39;&#39;&#39; is acyl, A is ethylene or methylmethylene and n is an integer of 2 or 3. The aminoalkanol esters and their pharmaceutically acceptable acid-addition salts are useful as medicaments for treatment of cardiovascular diseases.

United States Patent Kaneko et al.

" Oct. 24, 1972 1541 AMINOALKANOL ESTERS AND THEIR PHARMACEUTICALLYccERrAnLE ACID-ADDITION SALTS [2]] App]. N0.: 766,297

[30] Foreign Application Priority Data Oct. 13, 1967 Japan .;...42/65896061. 13, 1967 Japan ..42/65897 [52] us. c1 "260/2955 R, 260/473 R,260/476 R,

[51] 1m. (:1 ..C07d 31/34, 0076 69/78 [58] Field 61 Search..'.260/295.5, 473. R, 476 R [56] References Cited UNITED STATES PATENTS3,607,909 9/1971 Beregi et al. ..260/476 R 2,766,252-10/1956Schlesinger. ....'2 60/295.5

OTHER PUBLlCATlONS' Roberts et al., Basic Principlesof OrganicChemistry,

Benjamin Inc., pp.'-531, 535, 563 and 659, QD2SlR58 PrimaryExaminer-Alan L. Rotman Attbmey--Harry C. Bierman, Jordan B. Bier manand Bierman & Bierman 7] ABSTRACT Aminoalkanol esters of the formula:

cn-A-iI-mHM-om i 2. v s s .7 .7 s v.

wherein R is hydrogen or phenyl, R is hydrogen or alkyl having one tofour carbon atoms, R" is acyl, A is ethylene or methylmethylene and n isan integer of 2 or 3. The aminoalkanol esters and their pharmaceuticallyacceptable acid-addition salts are useful as medicaments for treatmentof cardiovascular diseases.

10 Claims, N0 Drawings wherein R is hydrogen or 'phenyl, R is hydrogenor alkyl having one to four carbon atoms (e.g. methyl, ethyl, propyl,isopropyl, butyl), R" is acyl, A is The term acyl hereinabove used isintended to mean the residue of a carboxylic acid (e.g. alkanoic acid,aromatic carboxylic acid, alicyclic carboxylic acid, heterocycliccarboxylic acid) excluding hydroxyl therefrom. The carboxylic acyl groupmay usually'have up to 12 carbon atoms and the specific examples are asfollows: lower alkanoyl (e.g. acetyl, propionyl, isopropionyl, butyryl),hydroxy-(lower)alkanoyl (e.g. hydroxyacetyl, B-hydroxypropionyl,-y-hydroxy butyryl), phenyl(lower)alkanoyl (e.g. phenylacetyl, [3-phenylpropionyl), phenyl-hydroxy(lower)a.lkanoyl (e.g.a-hydroxy-a-phenylacetyl, a-hydroxy-B-phenylpropionyl), benzoyl,hydroxybenzoyl (e.g. Z-hydroxybenzoyl, 4-hydroxybenzoyl), loweralkylbenzoyl (e.g. 2-methylbenzoyl, 4-methylbenzoyl), loweralkoxybenzoyl (e.g. 4-methoxybenzoyl, 4-ethoxybenzoyl,3,4-dimethoxybenzoyl, halobenzoyl (e.g. 4-chlorobenzoyl, 4-bromobenzoyl,4- fluorobcnzoyl), cyclo(lower)alkanoyl (e.g. cyclopentanoyl,cyclohexanoyl), lower alkylcyclo(lower)alkanoyl (e.g. camphonanyl,4-methylcyclohexanecarbonyl, pyridinecarbonyl (e.g. nicotinoyl), etc.

As the pharrnaceutically acceptable acid-addition salt of theaminoalkanol ester [1], there may be exemplified the following salts:hydrochloride, sulfate, nitrate, acetate, propionate, oxalate, tartrate,malonate, malate, maleate, citrate, lactate, gluconate, aspartate,glycolate, methoxyacetate, phenylacetate, etc.

It has now been found that the aminoalkanol esters [I] and theirpharmaceutically acceptable acid-addition salts generally andcharacteristically exhibit a variety of pharmacological activities suchas coronary vasodilator activity, spasmolytic activity and hypotensiveactivity, which ensure their usefulness as medicaments for treatment ofcardiovascular diseases. It is notable that the correspondingaminoalkanols have no practical potency in the saidpharmacologicalactivities.

ethylene or methylmethylene and n is an integer of 2 or 7 subsequentdescription.

Accordingly, a basic object of the present invention is to embody thenovel aminoalkanol esters [-I] and their pharmaceutically acceptableacid-addition salts. -Another object of this invention is to embody theaminoalkanol esters [l] and their pharmaceutically acceptableacid-addition salts having pharmacological activities/A further objectof the invention is to embody a process for preparing the aminoalka nolesters [I] and their pharmaceutically acceptable acid-addition salts.

A still further object of the invention is to embody a process forpreparing the aminoalkanol esters [I] and theirpharmaceuticallyacceptable acid-addition pharmaceuticallyacceptableacideaddition salts. These and other objects will be apparent to thoseconversant with the art to which the present invention pertains from theIn accordance with theqpresent invention, the

aminoalkanol ester [I] is prepared by condensing a.3,4,5-trimethoxybenzoyl), I

2,2,6-trimethylcyclohexanecarbonyl),

compound of the formula:

Zto leave a moiety of the formula:

in which R is as defined above in the resulting product with a compoundof the formula:

wherein n is as defined above, R"" is hydrogen or acyl and Z is a groupreactive with a group hereinbefore represented by the symbol Y to leavea moiety of the in which R is as defined above in the resulting product;when A is methylenecarbonyl, reducing the resulting product with areducing agent; when R" is hydrogen, reacting the resulting product withan acylating agent; and, when R is hydrogen, optionally reacting theresulting product with an alkylating agent.

Some of the concrete procedures fallen within the category of the aboveprocess are illustrated below.

- i I Procedure I QUE-A-Ji I'iN-(CHzh-OH 1'. 1 [III] [1V1QiH-A-r'I-tClLh-DH I v If I J l [H] CHANH X-(CHzh-OH 1 QCH-A-ILwmh-OR"wherein R, R',.R", A and r are each as defined as above and sha ssn (as:e llvti brcmln l- .1

As shown in the above scheme, the procedure con- 1 sists of condensationand esterfication. The condensation may be carried out by reacting thealkyl halide [III] with the alcohol [IV] or the amine [V] with thealcohol [VI], preferably in a solvent (e.g. methanol, ethanol, benzene,toluene, xylene) at a temperature from 100 to 200 C, if needed, in asealed tube or an autoclave. The reaction is normally accomplishedwithin several hours. The esterfication may be effected by reacting theresultant aminoalkanol [II] or its acidaddition salt with an organiccarboxylic acid or its reactive derivative such as acid halide, acidanhydride or acid lower alkyl ester, ordinarily in an inert solvent(e.gI benzene, toluene, xylene, chloroform) at a temperature from roomtemperature to 150 C. The reaction is usually accomplished withinseveral to 20 hours. When the reagent is an organic carboxylic aciditself, the use of a dehydrating agent (e.g. hydrogen chloride,p-toluenesulfonic acid, dicyclohexylcarbodiimide) is required. When anorganic carboxylic acid lower alkyl ester is employed as the reagent,the presence of an acidic catalyst (e.g. hydrogen chloride,p-toluenesulfonic acid) or a basic catalyst (e.g. sodium methoxide,sodium ethoxide) is essential.

4 wherein R, R, R", A, n and X are each as defined above.

As shown in the above scheme, the procedure con-' sists of condensation,reduction and esterification. The condensation may be accomplished byreacting the alkanoyl halide [VII] with the alcohol [IV] or the amide[Vlll] with the alcohol [VI] in a solvent (e.g. chloroform, carbontetrachloride), preferably in the presence of a base (e.g'.triet'hylamine, pyridine).while cooling with ice for several hours. Thesubsequent reduction may be executed by treating the amide [XX] with areducing agent conventionally employed for conversion of an amidecarbonyl group into a methylene group (ezg. lithium aluminum hydride,borane) in an inert solvent (e.g. dioxanefdiglyme, tetrahydrofuran),.usually' at a temperature from'room temperature to 120 C. Thereactiontis ordinarily ac- ;complished within several to 20 hours. The.subsequent esterification may be carried out in the entirely same anneras described in the procedure 1.

preferably in a solvent (e.g. methanol, ethanol,

benzene, toluene, xylene) at a temperature from to 200 C, if needed, ina sealed tube or an autoclave. The reaction is normally accomplishedwithin several hours.

Procedure 4 CHAI I(CHz)nOH /CH-AN(CHz)nOH R R [II/I] [II/II]/CHAN(OHz)nOR /CHAN(CHz),,-0R" R R [III] [IIII] wherein R, R, A and nare each as defined above and Table l R is alkyl having one to fourcarbon atoms (e.g. T d Com vasocilamracfivit methyl, ethyl, propyl,isopropyl, butyl). est ED y) ED 2) As shown 1n the above scheme, theprocedure consists of alkylation, followed or not by esterification. TheM3 3 Diphenylpmpylamino) alkylation may be executed by treating theaminoalethyi j 4 sq i th x b 'nzoate 3,8 30.0 kanol [II"] or theaminoalkanol ester [I"], both being l 1p eny propy ammo prepared byeither one of the procedures 1 to 1?, with an prowl 3,441,"!ethoxybenzoale 289 SM alkylating agent (e.g. formic acid-formalin, alkyl(hydrochloride) iodide, dialkyl sulfate), usually at a temperature fromggg gg fg l o 25 l 24 ro e 0 20 to 100 C. If necessary, a suitablesolvent may be (hydmchloflge) used depending on the kll'ld of thealkylating agent. In y p py wv the case of using formic acid-formalin,excess of formic f szig i g' l 2 T acid serves as a solvent. When alkyliodide is the re- 3-[N (3 3-Diphenylp opyl)-N-. agent, acetone, methanolor ethanol are examples of e y f g l p py the preferred solvent. Fordialkyl sulfate, the reaction Y E EZZ$ ,Z;S Q medium may be made ofether, chloroform, benzene or methylamino]ethyl acetate 5.25 the like inan alkaline condition. The esteriflcation to (Mame).

. 3-(3,3-Dlphenylpropy1ammo) be subsequently performed when theresulting product pmpyl mandelm (d t -n-ate) 38.0 is the ammoalkanol[Il"] may be effected in the enp y p py tirely same manner as describedin the procedure 1. 4o ethyl benmae (Mame) In the above procedures, theobjective aminoalkanol ester [I] is obtained in the form of free base oracid-addition salt. When the product is in the salt form, it can beconverted into the free base form by a conventional method, e.g.treatment of the former in chloroform with an aqueous solution of sodiumcarbonate. The treatment of the free base with an organic or inorganicacid (e. g. acetic acid, oxalic acid, malonic acid, tartaric acid, malicacid, citric acid, lactic acid, gluconic acid,

aspartic acid, hydrochloric acid, sulfuric acid, nitric acid) in asuitable solvent (e.g. water, methanol, ethanol) affords thecorresponding acid-addition salt.

As hereinbefore stated, the aminoalkanols [l] and their pharmaceuticallyacceptable acid-addition salts are useful as medicaments for treatmentof cardiovascular diseases. Some of the test results by which suchutility is confirmed are described below.

Test 1.

Coronary vasodilator activity:

A. On the isolated rats heart [cf. Setnikar et al.: Archivesinternationales de Pharrnacodynamie et de Therapie, 131, 187 (1961)].The hearts isolated from Wister rats of about 250 g body weight weresubjected to measurement of the coronary blood flow by the Langendorffmethod. The heart was perfused with Ringer- Locke solution, before whichthe test compound was given. The results are shown in Table 1. i

Note: 1 Dose oftest compound required for 20 increase of coronary B. Onthe isolated dogs heart [cf. Takenaka: Archiv fur ExperimentellePathologie und Pharmakologie, 252, 407 1966)]. The heart of a doganesthetized with intravenous injection of pentobarbital sodium (30mg/kg) was isolated and a glass cannula was inserted into each of theaorta and pulmonary artery. Another dog was anesthetized withintravenous injection of pentobarbital sodium (30 mg/kg) and dropphleoboclysis of physiological saline solution containing heparin, l0urethane and l chloralose and served as a donor. A cannula was insertedinto the common carotid artery of the donor animal and connected to theaortic cannula of the isolated heart. Perfusion pressure was measuredwith an electric manometer which was set between the carotid artery ofthe donor animal and the aortic cannula of the isolated heart. Thecoronary venous blood was allowed to flow out through the pulmonaryartery cannula into a blood reservoir and returned to the femoral veinof the donor animal. Cardiac contractions were recorded with a straingauge transducer, and electrocardiogram was recorded by I directinsertion of an electrode into the isolated heart.

On the donor animal, an electric manometer was set to the right femoralartery and the pressure was recorded. In the left femoral artery, a loopwas formed and an electronic manometer was set to record the femoralblood flow. The test compound was given intracoronarily. From theresultant data, the change percent of the coronary blood flow, theperfusion pressure and the coronary vascular resistance were calculated.The results are shown in Table II.

Test 2.

Spasmolytic activity:

A. Anti-acetylcholine, anti-histamine and anti-BaC1 activities. Theileum of a male guinea pig of 300 to 400 g body weight was isolated andcut to make strips of 1.5 to 2 cm in length. The strip was suspended inTyrod solution aerated and maintained at 28 C, and the contraction ofthe strip was recorded on a kymographion. One minute afteradministration of acetylcholine (10' g/ml), histamine (5 X g/ml) or BaCl(10 g/ml) and when the tonus rise became constant, the test compound wasacted on the strip and the antagonistic action to the tonus rise wasobserved.

B. Anti-serotonine activity. The test was carried out according to theGoddum-Hameed method [Goddum et a1.: British Journal of Pharmacology andChemotherapy, 9, 240 (1954)]. A half horn of the uterus isolated from aWister female rat of 150 to 200 g body weight was suspended in a m1Magnus tube. Serotonin creatinate (2 X10 g/ml) was administered atintervals of 7 minutes and, after the contraction was induced, the hornwas washed three times with a nutrient medium having the followingcomposition (g/L): NaCl 9.0, NaHCO 0.5, KCl 0.42, CaC1 0.06, MgC10.0025, glucose 0.25. The test compound was given 5 minutes beforeadministration of serotonin creatinate. The antagonistic action tocontraction was observed.

C. Anti-nicotine activity. The intestinal canal isolated from a guineapig was set as in the above 1) and nicotine (2 X 10 g/ml) wasadministered thereto so that contraction was induced. The test compoundwas given 5 minutes before administration of nicotine. The

taken as'an index.

TABLE I1 The results of the above tests are shown in Table 111.

TABLE III E D (pg/ml) antiacetylcholine activity Test CompoundAdrenergic neuron block activity antinicotine activity antiantisero-Batonin C1, aetaetivity antihistamine activity 2-(3,3-Dipheny1-propylam-ino ethyl 3 -trimethoxy-benzoate (hydrochloride) 3-(Z-Pheny1isopropy1amino)- propyl 3,4,5- trimethoxybenzoate(hydrochloride) Diphenylpropy1)-N- methylaminolpropyl 3 ,4,5-trimethoxybenzoate (oxalate Diphenylpropy1)-N- methy1amino[ethy1benzoate (oxalate) Diphenylpropyl )-N- methylaminolethyl acetate(oxalate) 3-( 3,3-Diphenylpr0pylarnino)- propyl mandelate (dtartrate)Test 3.

Hypotensive activity:

Both kidneys of Wistar male rats of about 250 g body weight were wrappedwith silk cloths, and the animals received 1 saline solution for about 1month whereby hypertensive state was induced. Then, the animals wereadministered orally the test compound. Blood pressure was measured, andthe depression percent was calculated [Page: The Journal of the AmericanMedical Association, 1 13,2046 (1939)]. The results are shown in TableIV.

Coronary blood flow (ml/min.)

Coronary vascular resistance After After Dose adminis- Change adminis-Change admlnis- Change Test compound 04g.) Control tration (percent)Control tration (percent) Control tration (percent) 1:: 22;: 2:2 is: 1&22:2 iii :22 2.122 :92 f -ig g 9 (hydm' 31. 9 44. 3 +43. 8 57. a 49. 2-16. s 1. s0 1. 11 -3s. 3 2 a 3 :1 l 1' h l 300 40. 8 53. 8 +32. 1 95. 762. 3 -36. 0 2. 35 1. 16 50. 6

- ip eny propy amino ct y 49 22;; 21;: +192 112 .92 42%*Qfiheqyliwpmpylaminm PYPY1 30 34 5 39 0 +13 0 5s 5 47 4 -19 0 1 7o 1 2"-28 g fif gg (hydm' 100 39. 0 41. 4 -15. 2 49. a 44: 1 -10. 5 1: 26 1101-15I i 2-[N-(3,3-di henylpropyD-N-methyl- 100 36.4 36.4 0 120 120 0 3.29 3.29 0 amino] et yl benzoate (oxalate). 300 37.6 41.4 +10 121 107.6-11. 1 3.22 2.60 19.3 2-1N-(3,3-dipheny1propy1)-N-methyl- 100 36. 4 36.4 0 110 0 3. 02 3.02 0

aminolethyl acetate (oxalate).

TABLE IV Time after administration (min.)

. Dose Test compound (mg) 30 60 120 1803-(3,3-diphenylpropylamino)-propyl 3,4dlmethoxybenzoate(hydrochloride)... 6.5 (-6.0) -1.3 (-1.2) (0) -2.6 (-2.5)3-(3,3-(41iiphenylpropylamino)-propyl 3,4,5-trimethoxybenzoate (bymmmde) 100 -11.3 10.7 11.7 (-17.o -1a.7 -13.0 -9.3 -9.o3-(2-phenylisopropylsrnino)-propyl 3,4,5-tnmethoxybenzoate Y(hydrochloride) 100 '-4.3 (4. 3) 12.5 (-12.0) -6.8 (-6.5) 6.8 (-6. 3)2-[N-(3,3-diphenylpropyl)-N-methylaminoIethyl benzoate (oxalate)- 100 -1(-1. 2) 1. 1 (-1. 1) 2. 3 (-2. 2) -7.4 (-7. 1)

-(3a p e ylp py (oxalate) jigjg 5:3 2; I 22 j 1 1, 2 1 3;? 1 3973;

N OTE.The numerals not parenthesized represent the values aboutdiastrolie blood ressure. The numerals parenthesized represent thevalues about systolic blood pressure.

The toxicity of the aminoalkanolesters [I] and their pharmaceuticallyacceptable acid-addition salts is' considerably low. In the acutetoxicity, for instance, the LD values of these compounds when orally orsubcutaneously administered to Wistar male rats and to lCR-JCL male micewere respectively more than 3,000 mg/kg and more than 2,000 mg/kg.Further, for instance, the LD values of3-(3,3-diphenylpropylamino)propyl 3,4,5-trimethoxybenzoate(hydrochloride) intravenously administered to Wistar male rats and toICR-JCL male mice were respectively 31.5 mg/kg and 35.0 mg/kg.

The aminoalkanol esters [I] and their pharmaceutically acceptableacid-addition salts can be administered by conventional methods,conventional types of unit dosages or with conventional pharmaceuticalcarriers to produce a therapeutic effect for cardiovascular diseases inhuman beings and animals. Thus, they can be used in the form ofpharmaceutical preparations, which contain them in admixture with apharmaceutical organic or inorganic carrier material suitable forenteral or parenteral applications. Oral administration by the use 'oftablets, capsules, powders or in liquid form such as suspensions,solutions, emulsions or syrups is particularly advantageous. When formedinto tablets, conventional excipients (e.g. sodium citrate, lactose,microcrystalline cellulose, starch), lubricating agents (e.g. anhydroussilicic acid, hydrized castor oil, magnesium stearate, sodium laurylsulfate, talc) and binding agents (e.g. starch paste, glucose, lactose,gum acacia, gelatin, mannitol, magnesium trisilicate, talc) used intherapeutic unit dosages can be employed. When administered as liquids,conventional liquid carriers can be used. For intravenous orintramuscular injection, those in acid-addition salt form, particularlyhydrochlorides, are employed after dissolving in water, if necessary,followed by buffering or making isotonic with glucose, saline or thelike.

The unit dosage or therapeutically effective quantity of thearninoalkanol esters [I] and their pharmaceutically acceptableacid-addition salts for human beings can vary over wide limits such asthat of about 0.1 to about 50 mg. It is indicated from animalexperiments that about 0.5 to about mg, more preferably about 2 i toabout 6 mg, of the therapeutic agent per kg of body weight is a suitabledaily dose for human adult. The dosage of the particular therapeuticagent used can vary considerably, such as the age of the patient and thedegree of therapeutic effect desired. In the case of solid preparations,each unit dosage form of the therapeutic agent can contain from about 5to about 95 of the same by weight of the entire composition with theremainder comprising conventional pharmaceutical carriers. When thetherapeutic agent is used an aqueous solution, i.e. injection, thesoution may contain about 0.05 to about 0.5 of the same by weight of theentire solution. Of course, it is possible to administer the therapeuticagent, i.e. the pure compound, 20 without the use of any pharmaceuticalcarrier.

7 Practical and presently preferred embodiments of the present inventionare illustratively shown in the followir slixas a a 1 Example 1 v I I A.In a sealed tube, a mixture of 1-chloro-3,3- diphenylpropane (2.5 g),3-aminopropan 1-o1 (1.0 g) and ethanol (20 ml) is heated at 130 C for6.5 hours. After removal of the ethanol from the reaction mixture, theresidue is dissolved in benzene, washed with water and extracted with 5hydrochloric acid and water in order. The washing water, thehydrochloric acid extract and the water extract are combined together,made alkaline with sodiumhydroxide and extracted with benzene. Thebenzene extract is washed with water, dired over anhydrous sodiumsulfate and concentrated to give 3-(3,3-diphenylpropylamino)propanl-ol(2.5 g). M.P. 88 to 90 C.

The starting l chloro-3,3-diphenylpropane is prepared as follows:3,3-diphenylpropan-l-ol (13.8 g) is dissolved in benzene (40 ml),admixed with thionyl chloride (20 g) and refluxed for 1 hour; excessofthionyl chloride is distilled off; and the resultant is distilledunder reduced pressure to give an oil (12.0 g) boiling at 146 to 147 C/4mmHg.

B. In a sealed tube, a mixture 'of 3,3-diphenylgpropylamine (5 g),3-chloropropan-1-ol (1.6 g) and ghanol (20 ml) is heated at 130 C for 8hours. The reaction mixture is treated as in (A) to give 3-(3,3- 50gihenyl opylaminoypropan-bol (3 g).

m Example 2.

A. A mixture of 2-(3,3-dipheny1propylamino)-ethanl-ol hydrochloride (1.5g), 3,4,5-trimethoxybenzoic 55 acid (1.0 g) and p-toluenesulfonic acid(2 g) in benzene (20 m1) is refluxed for 15 hours. After cooling,

the reaction mixture is washed with 5 sodium carbonate solution and 10hydrochloric acid, dried over anhydrous sodium sulfate and concentrated.The 0 residue is admixed with an ethanolic solution of hydrochloric acidand concentrated under reduced pressure. The residue is crystallizedfrom a mixture of ethanol and ether to give2-(3,3-diphenylpropylamino)ethyl 3,4,5-trimethoxybenzoate 65hydrochloride (0.75 g). M.P. 172 to 173 C.

B. 3-(3,3-Diphenylpropylamino)propan-l-ol hydrochloride (1.5 g), benzoicacid (1.0 g) and ptgluenesulfonic acid (2.0 g) are added to benzene (20l l ml), and the resultant mixture is treated as in (A). The obtainedcrude crystals are recrystallized from ethanol to give '3-(3,3diphenylpropylamino)propyl benzoate hydrochloride 1.5 g). M.P.- 178 to180 C.

C. 3-( 3,3-Diphenylpropylamino)propan-1-ol (1.5 g), 3,4-dimethoxybenzoicacid- (1.0 g) and p-toluenesulfonic acid (2.0 g) are added to tolueneml), and the resultant mixture is treated as in (A) to give 3-(3,3-diphenylpropylamino)propyl 3,4-dimethoxybenzoate hydrochloride (1.5 g).M.P. 137 to 138 C.

In the above procedure, the use of p-hydroxybenzoic acid in place of3,4-dimethoxybenzoic acid affords 3- (3,3-diphenylpropylamino)propylp-hydroxybenzoate hydrochloride. M.P. 131 to 134 C.

D. 3-( 3,3-Diphenylpropylamino)propan-1-ol 1.3 g),3,4,5-trimethoxybenzoic acid (1.0-g) and p-toluenesul fonic acid (2.0 g)are added to benzene (20 ml), and the resultant mixture is treated as in(A) to give 3-(3,3- diphenylpropylamino)propyl 3,4,5-trimethoxybenzoatehydrochloride 1.5 g). M.P. 145 to 147 C.

The hydrochloride is dissolved in chloroform. The resultant solution iswashed with sodium carbonate solution and concentrated to give3-(3,3-diphenylpropylamino)propyl 3,4,5-trimethoxybenzoate, which istreated with an aqueous or ethanolic solution of an acid to give thecorresponding acid-addition salt. Some examples of the acidadditionsalts thus obtained are as follows: oxalate, M.P. 179 to 181 C;malonate, M.P. 140 to 143 C; dl-malate, M.P. 91 to 94 C; d-tartrate,M.P. 54 to 60 C; citrate, M.P. 6 lto 66 C; dl-lactate, extremely lowmelting point; gluconate, extremely soluble in water, not crystallized;aspartate, extremely soluble in water, not crystallized; acetate, notcrystallized; nitrate, M.P. 139 to 140 C, sulfate, extremelyhygroscopic.

E. 2-(3,B-Diphenylpropylamino)ethan-l-ol (1.5 g), p-chlorobenzoic acid(1.0 g) and p-toluenesulfonic acid (2 g) are added to chloroform (20ml), and the resultant mixture is treated as in (A) to give 2-(3,3-diphenylpropylamino)ethyl p-chlorobenzoate hydrochloride (0.5 g).

In the similar manner, 3-(3,3-diphenylpropylamino)- propylp-fluorobenzoate hydrochloride is prepared from3-(3,3-diphenylpropylamino)propan-lol and, pfluorobenzoic acid. M.P. 221to 223 C.

F. 3-(2-Phenylisopropylamino)propan-l-ol (2.5 g),3,4,5-trimethoxybenzoic acid (2.5 g) and p-toluenesulfonic acid (5.0 g).are added to benzene (20 ml), and the resultant mixture is treated as in(A) to give 3-(2- phenylisopropylamino)propyl 3,4,5-trimethoxybenzoatehydrochloride (2.6 g). M.P. 138 to 141 C.

G. 2-[N-(3,3-Diphenylpropyl)-N- methylamino]ethan-l-ol hydrochloride(1.5 g), 3,4,5- trimethoxybenzoic acid (1.0 g) and p-toluenesulfonlcacid (2 g) are added to benzene (20ml), and the resultant mixture istreated as in (A) to give 2-[N-(3,3- diphenylpropyl)-N-methylamino]ethyl3,4,5- trimethoxybenzoate hydrochloride (0.8 g). M.P. 135 to 1 37 C. A

In the similar manner, 3-[N-(3,3-diphenylpropyl)-N- methylamino]propyl3,4,5-trimethoxybenzoate hydrochloride is prepared from3-[N-(3,3-diphenylpropyl)-N-methylamino]-propan-1-01 and 3,4,5-trimethoxybenzoic acid. The hydrochloride is dissolved in chloroform,washed with sodium carbonate solution, dried and nsem -Th ssiquq amixsqyith ethanolic solution of oxalic acid to give the oxalate.

methylamino]ethyl benzoate (2.5 g) as oil. The oil is dissolved inethanol, admixed with an ethanolic solution of oxalic acid and allowedto stand to give the oxalate. M.P'. 144 to 146 C. The use of anethanolicsolution of d-tartaric acid inplace of an ethanolic solution ofoxalic acid affords the d-tartrate. M.P. 101 to 105 C.

In the similar manner, 3-[N-(3,3-diphenylpropyl)-N- methylamino]propylbenzoate is prepared from 3-[N- (3,3-dipheny1propyl)-N-methylamino]propan-1-01 and benzoyl chloride.

I. A mixture of 2-[N-(3,3-diphenylpropyl)-N- methylamino]ethan-l-ol (1.9g) and acetic anhydride (10 ml) is heated at C for 2 hours. Aftercooling, the reaction mixture is admixed with water (50 ml), madealkaline with sodium carbonate and shaken with benzene. The benzenelayer is washed with water, dried over anhydrous sodium sulfate andconcentrated to give 2-[N-(3,3-diphenylpropyl)-N-methyl-amino]ethylacetate (2.1 g). The compound is dissolved in a'small amount of ethanol,admixed with an ethanolic solution of oxalic acid and allowed to standto give the oxalate. M.P. 140 to 142 C.

' In the similar, 3-[N+(3,3-diphenylpropyl)-N-methyl amino]propylacetate is prepared from 3-[N-(3,3 diphenyl-propyl )-N-methylamino]propan- 1 -ol and acetic anhydride. I

J. A mixture of 3-(3,3-diphenylpropylamino)- propan-l-ol (10 3), methyldI-mandelate (10 g)'and sodium p-toluenesulfonate monohydrate (25 g) inbenzene (200 ml) is refluxed on a water bath for 13 hours. Aftercooling, the reaction mixture is washed with dilute hydrochloric acid,water and sodium carbonate solution in order, dried over anhydroussodium sulfate and concentrated. The resulting oil is admixed with anethanolic solution of oxalic acid to give 3-(3,3-diphenylpropylamino)propyl dl-mandelate oxalate (13.0 g). M.P. 130 to131 C. The use ofan ethanolic solution of d-tartaric acid in place of anethanolic solution of oxalic acid affords the d-tartrate, M.P. 182 to 184 C.

K. A mixture of 3-(3,3-diphenylpropylamino)- propan-l-ol (2.7 g),nicotinic acid (1.4 g), toluenesulfonic acid (5.4 g) and benzene (40 ml)is heated on a water bath for 24 hours. After cooling, the reactionmixture is washed with 15 sodium carbonate solutionand shaken with 10hydrochloric acid. The aqueous layer is made alkaline with sodiumcarbonate and shaken with chloroform. The chloroform layer is dried overanhydrous sodium sulfate and concentrated. The residue is dissolved in asmall amount of chloroform and-subjected to chromatography on silicagel. The eluate is admixed with an ethanolic solution of oxalic acid,and the precipitate is crystallized from ethanol to give3-(3,3-diphenylpropylamino)propyl nicotinate oxalate (1.5 g). M.P. 173to 175 C (decomp.). Y

L. A mixture of 3-(3,3 diphenylpropylamino)- propan-l-ol (2.7- g),naphtenic acid (1.4 g) and ptoluenesulfonic acid (5.1 g) in benzene (20ml) is refluxed for 13 hours. After cooling, the reaction mixture iswashed with 15 sodium carbonate solution, 10 hydrochloric acid and 15sodium carbonate solution in order, dried over anhydrous sodium sulfateand concentrated. The residual oil is admixed with an ethanolic solutionof oxalic acid, andthe precipitated crystals are recrystallized fromethanol to give 3-(3,3-

diphenylpropylamino)propyl naphthenate oxalate (2.0

g). M.P. 158 to 163 C.

M. A mixture of 2-(3,3-diphenylpropylamino)ethanl-ol hydrochloride (1.5g), benzoic acid (1.0 g) and ptoluenesulfonic acid (2 g) in benzene (20ml) is refluxed for 16 hours. Aftercooling, the benzene layer isseparated, washed with 5 sodium carbonate solution, hydrochloric acidand 5 sodium carbonate solution in order, dried over anhydrous sodiumsulfate and concentrated underreduced pressure. The residue is admixedwith an ethanolic solution of oxalic acid, and the precipitated crystalsare collected and recrystallized from water to give2-(3,3-diphenylpropylamino)-ethyl benzoate oxalate (1 g). M.P. 193 to195 C.

Example 3.

A mixture of 3,3-diphenylpropionic acid (45 g) in .thionyl chloride (40ml) is refluxed for 2 hours to remove excess of thionyl chloride. Theobtained 3,3- diphenylpropiony] chloride is dissolved in chloroform (100ml), and the resultant solution is dropwise added to a cooled mixture ofethanolamine (30 g), triethylamine (35 g) and chloroform (150 ml) whilestirring. The reaction mixture is allowed to stand overnight. Theprecipitate is collected by filtration, washed with water andrecrystallized from benzene (100 ml) to give2-(3,3-diphenylpropionylamino)ethan-l-ol (31.5 g). M.P. 9lto 93 C.

To a suspension of lithium aluminum hydride (4.5 g) ..dioxansrllqqflh a9 m Qf.%- 3 :4 P Y propionylamino)ethan- 1 -ol 10 g) in dioxane (30 ml)is dropwise added, and the resultant mixture is stirred at roomtemperature for 2 hours and refluxed for 12 hours. To the reactionmixture cooled with ice, there is dropwise added water (9 ml), and theresulting mixture is warmed for 1 hour. The precipitate is collected byfiltration and washed with dioxane. The filtrate and the washing dioxaneare combined and concentrated under reduced pressure to give2-(3,3-diphenylpropylamino)- ethan-l-ol (9.5 g). M.P. 74 to 76 C. Thecompound is admixed with an ethanolic solution of hydrochloric acid andconcentrated under reduced pressure to give the hydrochloride. M.P.l54.5 to 155.5 C.

1n the similar manner, 3-(3,3-diphenylpropylamino)- propan-l-ol isobtained from 3-(3,3-diphenylpropionylamino-propanl-ol prepared byreacting 3,3- diphenylpropionyl chloride with 3-aminopropan-l-ol. M.P.88 to 90 C. The hydrochloride, M.P. 14l.5 to 143.5 C.

Example 4.

A solution of 3,3-diphenylpropylamine (2.0 g) and 3- chloropropylbenzoate (1.9 g) in xylene (8 ml) is heated at 130 C for 4 hours. Aftercooling, chloroform (20 ml) is added. The mixture is washed with dilutehydrochloric acid and water to remove the starting amine, dried overanhydrous sodium sulfate and concentrated to give3-(3.,3-diphenylpropylamino)propyl benzoate hydrochloride (2.5 g). M.P.178 to '1 80C.

Ewn A. To a solution of 3-(3,3-diphenylpropylamino)- propan-l-ol (1.0 g)in formic acid (2.5 ml), 37 formalin (2 ml) is added, and the resultantmixture is heated on a water bath for 5 hours. After addition of water(20 ml), the reaction mixture is made alkaline with sodium carbonate andshaken with benzene. The benzene layer is washed with saturated sodiumchloride solution, dried over anhydrous sodium sulfate'andcfoncentrated. The residue is' admixed with an ethanolic solution ofhydrochloric acidand concentrated under reduced pressure. The residue isdissolved in acetone,

admixed with ether and allowed to stand. The

precipitated crystals are collected by filtration to obtain 3-[N-(3,3-diphenylpropyl)-N- 'methylaminolpropan-l-ol hydroiodide (0.9 g). M.P.

182 to 184 C.

I C. To a solution of 2-(3,3-diphenylpropylamino)- ethan-l-ol (2.0 g) informic acid (7 ml), formalin (7 m1) is added, and the resultant mixtureis heated on a water bath for 3 hours. After cooling, the reactionmixture is admixed with water (20 ml), made alkaline with sodiumcarbonate and shaken with benzene. The benzene layeris washed withwater, dried over anhydrous sodium sulfate and concentrated. The residueis admixed with an ethanolic solution of hydrochloric acid andconcentrated. The residue is crystallized from a mixture of acetone andether to give 2-[N-(3,3- diphenylpropyl)-N-methylamino]ethan-l-olhydrochloride (2.1 g). M.P. 132 to 134 C.

D. To a solution of 3-(3,3-diphenylpropy1amino)- propyl3,4,5-trimethoxybenzoate (1.7 g) in formic acid (3 ml), there is addedformalin (3 ml), and the resultant mixture is heated on'a water bath for5 hours. The reaction mixture is admixed with water (30 ml), madealkaline with sodium carbonate and shaken with benzene. The benzenelayer is washed with water, dried over anhydrous sodium sulfate andconcentrated to give 3-[N-(3,3-dipheny1propyl)-N-methylaminolpropyl3,4,5-trimethoxybenzoate 1.7 g).

Example 6. g

Fine powder of 3-(3,3'diphenylpropylamino)propyl3,4,5-trimethoxybenzoate hydrochloride (250 g), lactose (350 g),purified microcrystalline cellulose (300 g), corn starch (50 g)anhydrous silicic acid (10 g),

magnesium stearate (20 g) and hydrized castor oil (20 i A 3-(3,3DiphenylprQpylamino)propyl g) are uniformly mixed and tableted in aconventional manner to make 10,000 tablets (each weighing mg), followedby sugar coating. Each of the sugar coated tablets thus tive ingredient.Example 7.

. 3 4 5 t r imethoxybenzoate hydrochloride (4 g) is dissolved inmethylaminolpropan-l-ol hydrochloride (0.9 g). M.P.

prepared contains 25 mg of the acdistilled water 1,000m1) and filtered.Each 2 ml of the solution is filled in an ampoule, which is thensterilized at l2l C for 20 minutes. Each of the ampoules thus obtainedcontains 8 mg of the active ingredient.

Example 8.

3-(3,3-Diphenylpropylamino)propyl 3,4,5- trimethoxybenzoatehydrochloride (10 g) is dissolved in distilled water (2,500 ml), andphysiological saline solution 17,500 ml) is added thereto. Afterfiltration, each 100 ml of the solution is filled in an ampoule, whichis then sterilized at 121 C for 20 minutes. Each of the ampoules thusobtained contains 50 mg of the active ingredient.

What is claimed is:

1. An aminoalkanol ester of the formula:

wherein R is hydrogen or phenyl, R is hydrogen or alkyl having one tofour carbon atoms, R" is cyclic acyl selected from the group consistingof 3,4,5-trimethoxybenzoyl, 3,4-di-methoxybenzoyl, benzoyl,a-hydroxybenzoyl and nicotinoyl, A is ethylene or methyl methylene and nis an integer of 2 or 3, or a pharmaceutically acceptable acid additionsalt thereof.

2. The aminoalkanol ester according to claim 1 wherein R is phenyl, R ishydrogen, R" is 3,4,5- trimethoxybenzoyl, A is ethylene and n is 3, or apharinaceutically acceptable acid addition salt thereof.

3. The aminoalkanol ester according to claim 1 wherein R is phenyl, R ishydrogen, R" is 3,4,

' maceutically acceptable acid addition salt thereof.

4.-'The aminoalkanol ester according to claim 1 wherein R is phenyl, Ris hydrogen, R" is 3,4- dimethoxybenzoyl, A is ethylene and n is 3, or aphar-, maceutically acceptable acid addition salt thereof.

5 The aminoalkanol esteraccording to claim 1' wherein R is hydrogen, Ris hydrogen, R" is 3.4,5-

lt imethoxybenzoyl, Ais methylmethyleneand'nis 3 ,or a pharmaceuticallyacceptable acid addition salt thereof.

6. The aminoalkanol ester according to claim l wherein R is phenyl, R'is methyl, R" is 3,4,5-. trimethoxybenzoyl, A is ethylene and n is 3, ora pharmaceutically acceptable acidaddition salt thereof.

- 7. The aminoalkanol ester according to claim 1 wherein R is phenyl, R'is methyl, R" is benzoyl, A is ethylene and nis 2, or a pharmaceuticallyacceptable acid addition salt thereof.

8. The aminalkanol ester according to claim 1 wherein R is phenyl," R ishydrogen, R" is a-hydroxybenzoyl, Ais ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof.

9. The aminoalkanol ester according to claim 1 wherein R is phenyl, R ishydrogen, R" is nicotinoyl, A is ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof. I 10. Theaminoalkanol ester according to claim 1 wherein R is phenyl, R' ishydrogen, R" is benzoyl, A is ethylene and n is 2, or a pharmaceuticallyacceptable acid addition salt thereof.

2. The aminoalkanol ester according to claim 1 wherein R is phenyl, R''is hydrogen, R'''' is 3,4,5-trimethoxybenzoyl, A is ethylene and n is 3,or a pharmaceutically acceptable acid addition salt thereof.
 3. Theaminoalkanol ester according to claim 1 wherein R is phenyl, R'' ishydrogen, R'''' is 3,4,5-trimethoxybenzoyl, A is ethylene and n is 2, ora pharmaceutically acceptable acid addition salt thereof.
 4. Theaminoalkanol ester according to claim 1 wherein R is phenyl, R'' ishydrogen, R'''' is 3,4-dimethoxybenzoyl, A is ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof.
 5. Theaminoalkanol ester according to claim 1 wherein R is hydrogen, R'' ishydrogen, R'''' is 3,4,5-trimethoxybenzoyl, A is methylmethylene and nis 3, or a pharmaceutically acceptable acid addition salt thereof. 6.The aminoalkanol ester according to claim 1 wherein R is phenyl, R'' ismethyl, R'''' is 3,4,5-trimethoxybenzoyl, A is ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof.
 7. Theaminoalkanol ester according to claim 1 wherein R Is phenyl, R'' ismethyl, R'''' is benzoyl, A is ethylene and n is 2, or apharmaceutically acceptable acid addition salt thereof.
 8. Theaminalkanol ester according to claim 1 wherein R is phenyl, R'' ishydrogen, R'''' is Alpha -hydroxybenzoyl, A is ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof.
 9. Theaminoalkanol ester according to claim 1 wherein R is phenyl, R'' ishydrogen, R'''' is nicotinoyl, A is ethylene and n is 3, or apharmaceutically acceptable acid addition salt thereof.
 10. Theaminoalkanol ester according to claim 1 wherein R is phenyl, R'' ishydrogen, R'''' is benzoyl, A is ethylene and n is 2, or apharmaceutically acceptable acid addition salt thereof.